Neuronal nicotinic receptors (nAChRs) hold very considerable promise as therapeutic targets for treatments of disorders of the CNS and peripheral nervous systems. Drugs aimed at nAChRs have potential for the treatment of neurodegenerative disorders, dyskinesias, Tourette's syndrome, schizophrenia, attention deficit disorder, anxiety and pain, as well as nicotine addiction. Our overall objective is to address the deficiency in drugs selective for nAChR subtypes. To do this, we will carry out studies to synthesize and/or chemically modify molecules belonging to one of several families of products known to have high affinities for nAChRs. Each of the chemical entities that is prepared will be evaluated in a battery of assays to measure its binding affinity at seven different nAChR receptor subtypes stably expressed in mammalian cells and to determine its functional activity as an agonist, competitive antagonist or noncompetitive antagonist. The goals of this research are to provide new pharmacological tools for studies of these receptors and the critical structure activity information that can lead or contribute to the development of nAChR subtype selective drugs to treat human diseases. To meet these objectives, we will pursue the following specific aims: To conduct synthesis and chemical modifications based on molecules already known to possess important properties at nAChR, namely: epibatidine (a high affinity agonist at all nAChR subtypes tested except alpha7), cytosine (an agonist at receptors containing beta4 subunits and a partial agonist at receptors containing beta2subunits), A-85380 (a high affinity agonist at receptors beta subunits), and erysodine (a competitive antagonist with high affinity for receptors containing beta subunits). To characterize each of the ligands prepared in the chemistry effort for their ability to act at nicotinic receptors by assaying its binding affinities at seven nAChR subtypes stably expressed in mammalian cells, and to determine if it has agonist, competitive antagonist or noncompetitive antagonist activity. Functional activity will be evaluated using established 86RbC1 efflux assays and/or whole cell patch clamp measurements.